Cytokines play important roles in the regulation of the immune system, including anti-tumor immune responses. A number of cytokines have been shown to have anti-tumor potential. Among these cytokines, interleukin-15 (IL-15) has been extensively studied as a promising anti-tumor candidate. IL-15 belongs to the common receptor γ-chain cytokine family that also includes IL-2. IL-15 and IL-12 share the γ- and γ-chains of their receptors (IL-2/15βγ), but bind to different a receptor chains (IL-2Rα/IL-15Rα). IL-15 binds to IL-15Rα expressed on antigen presenting cells and the IL-15/IL-15 Rα complex then binds to the IL-15βγ complex expressed on nearby effector cells. Similar to IL-12, IL-15 can stimulate the proliferation of T cells and natural killer (NK) cells, the expansion of cytotoxic T cells and the activation of NK cells. Unlike IL-12, IL-15 is not involved in the activation-induced cell death and maintenance of regulatory T cells, which can block the therapeutic effects of IL-2. Thus, IL-15 is ranked at the top of the National Cancer Institute's list of agents with great potential for cancer immunotherapy.
However, recent studies have suggested that in vivo anti-tumor effects of IL-15 could only be achieved at high dosage. Another limitation of IL-15 as a therapeutic agent is its short plasma half-life. One potential limitation of these efforts is that the function of IL-15 is systemic and not tumor specific. In response to a long IL-15 half-life, cytotoxic T cells or NK cells are expanded systemically, not only in tumors. As uncontrolled systemic activation of the immune system can be very toxic and lethal, a more desirable therapeutic agent will need to be able to limit its function to tumors and spare other tissues to reduce toxicity. Therefore, an ideal candidate should be tumor-targeting without substantial affects to normal tissues.